Emphysema Phenotype Research Articles

Pathophysiology of airflow limitation in chronic obstructive pulmonary disease

The airflow limitation that defines chronic obstructive pulmonary disease (COPD) is the result of a prolonged time constant for lung emptying, caused by increased resistance of the small conducting airways and increased compliance of the lung as a result of emphysematous destruction. These lesions are associated with a chronic innate and adaptive inflammatory immune response of the host to a lifetime exposure to inhaled toxic gases and particles. Processes contributing to obstruction in the small conducting airways include disruption of the epithelial barrier, interference with mucociliary clearance apparatus that results in accumulation of inflammatory mucous exudates in the small airway lumen, infiltration of the airway walls by inflammatory cells, and deposition of connective tissue in the airway wall. This remodelling and repair thickens the airway walls, reduces lumen calibre, and restricts the normal increase in calibre produced by lung inflation. Emphysematous lung destruction is associated with an infiltration of the same type of inflammatory cells found in the airways. The centrilobular pattern of emphysematous destruction is most closely associated with cigarette smoking, and although it is initially focused on respiratory bronchioles, separate lesions coalesce to destroy large volumes of lung tissue. The panacinar pattern of emphysema is characterised by a more even involvement of the acinus and is associated with alpha1 antitrypsin deficiency. The technology needed to diagnose and quantitate the individual small airway and emphysema phenotypes present in people with COPD is being developed, and should prove helpful in the assessment of therapeutic interventions designed to modify the progress of either phenotype.

Genetics of COPD

COPD is a complex mix of signs and symptoms in patients with chronic bronchitis and emphysema, diseases that largely result from cigarette smoking. Not all smokers, however, acquire COPD, and COPD can develop in nonsmokers. In the United States, COPD is currently the fourth leading cause of death. Surprisingly, there are no effective drug therapies for COPD that are able to significantly alter disease progression, and little is known of the underlying molecular mechanisms that are responsible for its occurrence. Candidate gene-association studies and linkage analyses have been reported for COPD patients. This review describes the genetic predisposition of healthy subjects or relatives of COPD patients to acquire COPD. In addition, the genetic bases of COPD with rapid decline of FEV1 are described, and the current genetic data that have been distilled from studies of COPD patients with a predominant emphysema phenotype, with chronic bronchitis phenotype, and with a response to bronchodilators are discussed.

EMPHYSEMATOUS CHANGES ARE CAUSED BY DEGRADATION OF TYPE III COLLAGEN IN TRANSGENIC MICE EXPRESSING MMP-1

Disruption of the extracellular matrix is believed to play an important role in the pathogenesis of emphysema. Prior studies have demonstrated that transgenic mice expressing the human tissue collagenase, matrix metalloproteinase 1 (MMP-1), develop emphysema. MMP-1 is a protease with substrate specificity for fibrillar collagen. Type I and III collagens, which are the most abundant proteins within the lungs, are the primary substrates for MMP-1. To assess if type I collagen was indeed the site of action for MMP-1 in these transgenic mice, hybrid mice were generated by crossing the MMP-1 transgenic mice with mice that had degradation-resistant type I collagen. The hybrid mice demonstrated an identical emphysematous phenotype as the MMP-1 transgenic mice, indicating that the degradation of type I collagen was not essential to the development of emphysema in these mice. Immunohistochemical studies in control mice demonstrated that collagen fibers in the alveolar walls and ducts of the normal mouse lungs consist mainly of type III collagen. In the transgenic and hybrid mice, the emphysematous changes, which developed, were associated with a marked decrease in type III collagen in these alveolar structures. These results indicate that MMP-1 generated the emphysematous phenotype via the degradative effect on type III collagen, which is a vital structural element of the alveolar walls. This is the first study to show that a matrix metalloproteinase may cause emphysema via its effects on a specific collagen subtype. As such, it should provide important insight into the mechanisms of this disease in humans.

Relation of serum elastin peptide concentration to age, FEV1, smoking habits, alcohol consumption, and protease inhibitor phenotype: an epidemiological study in working men.

In clinical investigations elastin peptide concentration has been proposed as one potential marker of lung elastin degradation. No epidemiological study has yet confirmed this hypothesis. The relation of elastin peptide concentration to some factors closely related to pulmonary emphysema (age, smoking habits, FEV1 alpha protease inhibitor (PI) phenotype) and to alcohol consumption was examined in an epidemiological study of 310 working men. The elastin peptides used for obtaining antibodies and as reference in an ELISA assay were prepared from chemically hydrolysed elastin. The elastin peptide concentration significantly decreased with age from 2.92 (1.54) micrograms/ml among subjects younger than 30 years to 2.18 (1.14) micrograms/ml among subjects older than 50. Elastin peptide concentration did not differ with smoking habits and was clearly unrelated to FEV1. A lower elastin peptide concentration was observed in all groups of subjects with a protease inhibitor phenotype other than PI MM (PI FM, IM, MP, MS, MZ, and S phenotypes). The results cast doubts on the usefulness of the elastin peptide concentration as a marker of lung destruction in middle aged, predominantly healthy men. Blood elastin peptide concentration may reflect both elastin degradation and resynthesis. The results of this analysis suggest that several factors (age, alcohol consumption, non-PI MM phenotype) may be associated with decreased resynthesis of lung elastin. Further studies, conducted in various age groups and including estimates of the degree of lung destruction, are needed to unravel the mechanisms underlying lysis and resynthesis of lung elastin.